Abstract: Genomic technologies including expression microarrays and genotyping platforms offer unprecedented opportunities to advance our understanding of the contribution of environmental, genetic, and epigenetic factors towards modification of disease progression. Towards this end, we propose to use an integrative genomics approach to identify differentially expressed genes and their biologically relevant genetic variation impacting clinical severity in cystic fibrosis (CF), an inherited multisystem disease characterized by progressive deterioration in lung function and pancreatic insufficiency attributed to dysfunction of a single gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). In 2001, Jansen and Nap proposed combining genome-wide expression data with population genetics to identify sequence variants that regulate gene expression and in turn impact clinical phenotypes. Our premise is that such an approach is relevant to understanding the pathogenic mechanisms responsible for CF and chronic inflammatory lung diseases in general. Our unique multicenter collaboration, incorporating CF patients enrolled in the Wisconsin Newborn Screening Program, will ensure needed longitudinal follow-up of young patients necessary to confirm current findings and define complex associations. The resulting data will define a molecular phenotype of genes involved in early infections of the CF lung by P. aeruginosa and the contribution of host response to clinical outcome. This project has several important implications for identification of functional genetic variation in novel molecular targets and development of novel clinical diagnostic and prognostic tools. Public Health Relevance: Cystic fibrosis (CF) lung disease is characterized by chronic infection by Pseudomonas aeruginosa and is the major cause of morbidity and mortality in CF patients. The resulting data will define a molecular phenotype of genes involved in early infections of the CF lung by P. aeruginosa and the contribution of host response to clinical outcome. This project has several important implications for identification of functional genetic variation in novel molecular targets and development of novel clinical diagnostic and prognostic tools.